Cryptococcus neoformans is a pathogenic yeast which belongs to Basidiomycetes, a taxonomic Class phylogenetically remote from the rest of the pathogenic yeasts (Ascomycetes). C. neoformans causes fatal meningoencephalitis primarily in patients with T- lymphocyte dysfunction and is the only species in the genus Cryptococcus that has optimum growth at temperatures higher than 30C. Although extensive studies on the molecular basis of cell cycle and morphogenesis have been carried out in ascomycetous yeasts, such studies have not been conducted in C. neoformans. This project was initiated to study the molecular genetics of cell cycle associated genes in C. neoformans. In 2003, we reported the function of the gene CCN1 which was necessary for cell growth at 37C. During 2004-2005,we studied the effect of TUP1 deletion on the biology of MATa and MATalpha strains in serotype D. TUP1 is a global regulator, which is known to control morphogenesis in many ascomycetous fungi. Interestingly, tup1 mutants manifested quorum sensing (QS) and at growth temperatures that allow QS function, it differed between MATa and MATalpha strains. An 11-mer peptide secreted in the growth medium of tup1 mutant was identified as the quorum sensing molecule. Fungal QS factors reported thus far have been alcohols such as tyrosol or farnesol but a peptide has never been reported as a QS factor in the Kingdom Fungi.During 2005-2006, we deleted TUP1 from a serotype A strain of C. neoformans which differs from serotype D strains in capsular antigenicity and the function of various genes. Unlike in serotype D strains, tup1 deletion in H99 caused no quorum sensning-like phenotype but the growth on complex media was clearly retarded compared to the wild type. Tup1 ko strain of serotype A showed a drastic increas in capsule formation and when the tup1 ko strains were complemented with the wild type TUP1 gene, the capsule size decreased significantly compared to the tup1 ko strains. These findings indicate that TUP1 represses capsule formation in vitro. The capsule size in vivo, however, was not affected by TUP1 deletion. Mice infected with the tup1 ko strain survived much longer than either the wild type or the tup1 ko strain complemented with the TUP1 gene. This gene is the first, thus far, known to regulate capsule formation in C. neoformans.